Recent studies in rodents have demonstrated that the immune, nervous and endocrine systems may function in an interdependent manner. Receptors for neural peptides and neuroendocrine hormones have been found on lymphoid cells. Some secretory products originating from the immune system, particularly, the lymphokine, interleukin-1 (IL-1), are able to affect classical endocrine hormone responses. Administration of IL-1 into adult rodents has provoked an increase in circulating levels of ACTH and glucocorticoids. Glucocorticoids, in turn, are able to regulate the monocyte secretion of IL-1. The specific aims of this project relate to investigation of the possibility that this interdependent regulatory pathway exists in the primate fetus and, considering the role of IL-1 as a growth factor in rapidly growing tissue, that IL-1 may also be important in the ontogeny of the fetal neuroendocrine response. The specific aims of this project are: 1) Determine whether the human fetus can synthesize and secrete IL-1, 2) Determine whether fetal monocyte secretions and specifically IL-1, can mediate fetal primate hypothalamic, pituitary, adrenal and/or gonadal response, 3) Determine whether fetal endocrine secretions can provide regulatory feedback inhibition of IL-1, 4) Determine the stage of gestation when these relationships become established. Methods used to explore these hypotheses include administration of endotoxin to stimulate IL-1 secretion in tissue cultures of fetal hypothalamus, pituitary, adrenal, and gonad, administration of IL-1 alpha and beta in tissue culture and perifusion in the presence of cofactors, e.g. GnRH in the pituitary, use of immunohistochemical and in-situ hybridization techniques to localize IL-1 within particular cell types, and use of hybridization protection assays to detect IL-1 and study transcriptional regulation within various fetal tissues. The principal investigator has a research background comprising clinical and basic science interests in immunology and reproductive biology. Most recently, as a recipient of an NIH NRSA fellowship award, he has been studying the ontogeny of the fetal LH response. The research site will be the University of California, San Francisco, Reproductive Endocrinology Center, under sponsorship of Dr. Robert B. Jaffe, Chairman of the Department of Obstetrics, Gynecology and Reproductive Sciences, and Director of the Reproductive Endocrinology Center. This well-equipped facility has an animal research unit and major equipment necessary to support a major research emphasis in fetal neuroendocrinology and the biochemistry, neuroanatomy, and physiology of the fetal hormonal milieu.